Dato-DXd Provides PFS Benefit in HR+/HER2– Breast Cancer

Datopotamab deruxtecan (Dato-DXd; DS-1062a) elicited a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs chemotherapy for patients with hormone receptor–positive, HER2-low or -negative metastatic breast cancer, according to data from the phase 3 TROPION-Breast01 trial (NCT05104866) presented the 2023 ESMO Congress.

“Overall results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor–positive breast cancer,” Aditya Bardia, MD, MPH, the director of the Breast Cancer Research Program at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School, in Boston, said during a presentation of the data.

Improved Survival With Dato-DXd

Patients who received Dato-DXd (n = 365) achieved a median PFS of 6.9 months (95% CI, 5.7-7.4) compared with 4.9 months (95% CI, 4.2-5.5) for those treated with investigator’s choice of chemotherapy (ICC; n = 367), reducing the risk for disease progression by 37% (HR, 0.63; 95% CI, 0.52-0.76; P < .0001), meeting the trial’s coprimary end point.

“After a small initial drop, there’s a separation between the curves in favor of Dato-DXd; [PFS is] maintained over time and, if anything, increases over time,” Bardia said, adding that the 9-month PFS rates were almost double with Dato-DXd compared with ICC. The 6-, 9-, and 12-month PFS rates with Dato-DXd were 53.3%, 37.5%, and 25.5%, respectively, compared with 38.5%, 18.7%, and 14.6% with ICC, respectively.

PFS benefit was seen across all subgroups, including those examining age, race, ECOG performance status, geographic region, number of previous lines of chemotherapy, prior use of CDK4/6 inhibitors, and prior use of taxane and/or anthracyclines.

Objective response rate was also superior with Dato-DXd at 36.4%, including a 0.5% complete response (CR) rate, compared with 22.9% in the ICC arm, which had no CRs.

Although the overall survival (OS) data are not mature at a median follow-up of 9.7 months, there was a trend that favored Dato-DXd over ICC (HR, 0.84; 95% CI, 0.62-1.14). “The study is continuing to the next planned analysis for overall survival,” Bardia added.

Additional Findings and Patient Baseline Characteristics

Median treatment duration was 6.7 months in the Dato-DXd arm and 4.1 months in the ICC arm. After a median follow-up of 10.8 months, 93 patients in the Dato-DXd arm and 39 in the ICC arm were still receiving study treatment. In both arms, treatment was discontinued (267 vs 240 patients) as a result of progressive disease (229 vs 240), adverse effects (AEs; 11 vs 10), patient decision (13 vs 32), death (2 vs 7), or other (12 vs 23).

“Two important points to note—as of data cutoff, approximately 3 times the number of patients are still [receiving] Dato-DXd as compared with the standard chemotherapy arm. [Additionally, the] majority of patients who discontinued the study had disease progression,” Bardia said.

The open-label, global TROPION-Breast01 trial randomly assigned patients 1:1 to receive either 6 mg/kg Dato-DXd intravenously every 3 weeks or ICC. ICC was comprised of eribulin mesylate on days 1 and 8 every 3 weeks (n = 220), vinorelbine on days 1 and 8 every 3 weeks (n = 38), gemcitabine on days 1 and 8 every 3 weeks (n = 33), or capecitabine on days 1 through 14 every 3 weeks (n = 76). Treatment in both arms continued until progressive disease, unacceptable tolerability, or other discontinuation criteria.

Patients were stratified by prior CDK4/6 inhibitor exposure (yes vs no), lines of chemotherapy received (1 vs 2), and geographic location (United States, Canada, and Europe vs rest of world).

Patients with hormone receptor–positive, HER2-negative (defined as immunohistochemistry 0/1+/2+; ISH negative) breast cancer who previously received 1 to 2 lines of chemotherapy were eligible for the trial. Additionally, patients enrolled had an ECOG performance status of 0 or 1 and either experienced progression on endocrine therapy (ET) or had ET deemed an unsuitable treatment option.

PFS by blinded independent central review per RECIST 1.1 criteria and OS served as the primary end points, while secondary end points included investigator-assessed PFS and safety.

Baseline characteristics were well balanced between arms. In the Dato-DXd arm, the median age was 56 years (range, 29-86) and the majority of patients were White (49%). In total, 63% of patients had received 1 prior line of chemotherapy and 37% had received 2 lines, 82% had received a CDK4/6 inhibitor, and 90% had received a taxane and/or anthracycline.

Of the 1003 patients screened, 732 underwent treatment randomization. “After screening approximately 1000 patients over the period of 1 year, the study enrolled rapidly. In a span of 1 year there were 732 patients who were randomly assigned. It highlights the interest in the study and the unmet need,” Bardia explained.

Dato-DXd Demonstrates Favorable Safety Profile

Treatment-related AEs (TRAEs) occurred in 94% and 86% of the Dato-DXd (n = 360) and ICC (n = 351) safety populations. However, the rate of grade 3 or higher TRAEs was less than half with the TROP2-directed antibody–drug conjugate (ADC) vs ICC (21% vs 45%, respectively).

TRAEs led to dose reductions in 21% of the Dato-DXd arm compared with 30% in the ICC arm; dose interruptions in 12% and 25%, respectively; and treatment discontinuation in 3% of each arm. One patient death occurred in the ICC group due to a TRAE. Serious TRAEs occurred in 6% of the Dato-DXd arm and 9% of the ICC arm.

Bardia highlighted that most TRAEs were grade 1 or 2. In the Dato-DXd and ICC arms, any grade TRAEs included anemia (11% vs 20%, respectively), neutropenia (11% vs 42%), dry eye (22% vs 8%), nausea (51% vs 24%), stomatitis (50% vs 13%), vomiting (20% vs 8%), constipation (18% vs 9%), fatigue (24% vs 18%), and alopecia (36% vs 21%). Oral mucositis/stomatitis and dry eye led to treatment discontinuation in 1 patient each in the Dato-DXd group; however, adjudicated drug-related interstitial lung disease rate rates were low and mostly grade 1 or 2 in this arm.

Addressing an Unmet Need

Bardia noted that despite the availability of newer treatment options in breast cancer, an unmet need remains for those with endocrine-resistant, metastatic disease. Although chemotherapy is widely used for this patient population, it is associated with a low response rate, poor prognosis, and significant toxicity; similarly, TROP2-directed ADCs that are either approved or are in development have demonstrated efficacy but may have toxicities leading to treatment limitations.

“From a field perspective, there’s an unmet need, both from an efficacy perspective as well as a toxicity perspective. We need agents that are better and less toxic,” Bardia said, adding that Dato-DXd may have unique properties to address these needs, such as its optimized drug to antibody ratio, stable linker payload, tumor-selective cleavable linker, and bystander antitumor effect.

Editor’s Note: Dr Bardia has participated in advisory boards for Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, and Foundation Medicine. He has also received research grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Natera, and Eli Lilly.

Reference

Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously treated inoperable or metastatic hormone receptor–positive, HER2-negative (HR+/HER2–) breast cancer (BC): primary results from the randomised phase III TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl 2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015